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Childhood Soft Tissue Sarcoma Treatment (PDQ®)- Patient version

This PDQ cancer information summary has current information about the treatment of childhood soft tissue sarcoma. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Childhood Soft Tissue Sarcoma Treatment (PDQ®)- Health Professional version

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood soft tissue sarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

2019 ASCO Annual Meeting

2019 CTOS Annual Meeting

PAPERS
 
SAFETY AND FEASIBILITY OF MAGNETIC RESONANCE-GUIDED HIGH INTENSITY FOCUSED ULTRASOUND
(MR-HIFU) FOR THE ABLATION OF RELAPSED OR REFRACTORY PEDIATRIC SOLID TUMORS INCLUDING
DESMOID TUMORS
AeRang Kim, MD, PhD1; Karun V. Sharma2; Pavel Yarmolenko3; James I. Geller4; Joseph G. Pressey4; John M. Racadio5; Haydar Celik3; Avinash Eranki3; Matthew Lanier6; Caitlin Tydings1; Ari Partanen7; Peter C. Kim8
1Oncology, Childrens National Medical Center, Washington, USA; 2Interventional Radiology, Children’s National Medical Center, Washington, , USA; 3The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Medical Center, Washington, USA; 4Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;
5Interventional Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 6Imaging Research Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 7Profound Medical Inc., Mississauga, ON, Canada; 8Surgery, George Washington School of Medicine, Washington, USA
Objective: Acute and late effects of current multi-modal therapy in pediatric cancer are substantial, and the prognosis for recurrent/refractory sarcomas and solid tumors remains dismal. Magnetic resonance guided high intensity focused ultrasound (MR-HIFU) is an ultrasound-based technology that can raise tissue temperature with millimeter spatial accuracy under MR thermometry guidance. Advantages over conventional local tumor control such as surgery or radiation therapy are that MR-HIFU is non-invasive, non-ionizing, and enables ablation of large tumor volumes under real-time image guidance. MR-HIFU has been studied in a variety of solid tumors in adults and for the relief of pain from bone metastases. There is evidence that MR-HIFU may improve systemic disease control by stimulating an anti-tumor immune response. The primary objective of this clinical trial is to determine the safety and feasibility of MR-HIFU ablation in children, adolescents, and young adults with relapsed/refractory solid tumors. Secondary objectives include the evaluation of changes in functional imaging, quality of life, and immune markers in children treated with MR-HIFU.
Methods: In this multi-institutional trial (NCT02076906), patients ≤ 30 years of age with relapsed/refractory solid tumors including desmoid tumors are eligible. Tumor target lesions are limited to those located in or close to bone at sites accessible to MR-HIFU. Patients with target lesions in the skull or spine or patients with any contraindication for MRI are excluded. Patient imaging and eligibility are reviewed by our multi-disciplinary HIFU team. Patients undergo MR-HIFU treatment of the selected lesion(s) under general anesthesia. Tolerability is defined during the 14 days following MR-HIFU ablation. Disease status is evaluated using standard imaging techniques post-treatment. Quality of life assessments using patient reported outcomes and immune pharmacodynamic markers are collected at baseline and during interval follow-ups post-treatment.
Results: Eleven evaluable patients [6M, 5F; median age 14 years (range 4-21)] with osteosarcoma (n=1), Ewing sarcoma (n=1), rhabdomyosarcoma (n=1), and desmoid tumor (n=8) have enrolled to date at two treatment centers. A total of 17 HIFU treatments were administered (2 patients underwent ablation of another target lesion, 2 patients underwent ablation of the same incompletely treated target lesion, one patient underwent ablation of the same target lesion 3 times). Only two HIFU treatments were technically unsuccessful due to the inability to achieve ablative temperature at the target location. There was no treatment limiting toxicities. One patient had a grade 3 skin burn requiring debridement. All other related toxicities were mild (grade 1/2) and reversible including transient pain (n=4), first or second degree skin burn (n=3); and transient paresthesia, neuropathy, skin discoloration, and gait disturbance due to pain (n=1 each). One target lesion was completely ablated; however, the patient progressed at other sites of disease. All other target lesions were partially ablated, either due to technical limitations or nearby critical structures.
Conclusion: MR-HIFU ablation of solid tumors in children, adolescents, and young adults appears to be safe and feasible. Changes in quality of life patient reported outcomes and immune markers’ analyses are underway. Tumor volumetric analysis of perfusion for disease response post ablation therapy is being evaluated.
 
POSTERS
 
Poster #335 3214469
SANDWICH ISOLATION SURGERY PREVENTS LOCAL RECURRENCE IN PROGRESSIVE DESMOID TUMORS: A PILOT OBSERVATIONAL STUDY
Junqiang Yin; Yiwei Fu; Changye Zou; Gang Huang; Jingnan Shen
The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
Objective: Desmoid tumors are highly recurrent especially when involving nerves and blood vessels. Isolating desmoid tumors from normal tissues with artificial barriers may deprive desmoid tumors of nutrients. The aim of this observational study was to prospectively assess the efficacy of a new surgery technique, named as sandwich isolation surgery, on preventing the local recurrence of progressive desmoid tumors.
Methods: Patients with progressive desmoid tumor involving adjacent nerves and blood vessels and received sandwich isolation surgery were eligible for enrolment. Sandwich isolation surgery refers to using a biomaterial un-absorbable patch to envelop involved neurovascular bundles after marginal or intralesional excision of desmoid tumors, isolating residual tumor or tumor bed from normal tissue, and forming a “normal tissue- biomaterial patch -tumor/tumor bed- neurovascular sheath” sandwich structure.
Results: Nine patients were included in the study. Among them, six had recurrent tumors and received at least once resection surgery before sandwich isolation surgery. These patients were followed up for 16.7-56.7 months (median: 31.6 months). After the sandwich isolation surgeries, no local recurrence was observed in eight of them. As for the rest one with local recurrence 11.5 month after excision, magnetic resonance images demonstrated that recurrent tumor was located only in the region where neurovascular bundles were not isolated. No adverse event associated with the enclosed neurovascular bundles was observed in all patients.
Conclusion: Sandwich isolation surgery was a new and low-cost technique to prevent the local recurrence of desmoid tumors, even if residual tumors remain around neurovascular bundles, which avoided functional impairment caused by repeated operations.
 
Poster #010 3250654
DESMOID TUMOR VOLUMETRIC ANALYSIS FOR DISEASE RESPONSE POST ABLATION WITH MAGNETIC RESONANCE GUIDED HIGH INTENSITY FOCUSED ULTRASOUND (MR-HIFU)
Caitlin Tydings1; Pavel Yarmolenko1; James I. Geller2; Joseph G. Pressey2; John M. Racadio2; Haydar Celik1;
Avinash Eranki1; Matthew Lanier2; Karun V. Sharma1; AeRang Kim1
1Children’s National Medical Center, Washington, USA;
2Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Objective: An objective measure of treatment response is an important feature of the clinical evaluation of cancer therapy. Response Evaluation Criteria in Solid Tumors (RECIST) is a unidimensional measurement that is currently the most widely accepted method of measuring treatment response. This may be suitable for more uniform, rapidly growing, malignant solid tumors; however, its limitations are most notable in irregularly shaped, heterogeneous tumors, particularly when treated using targeted or local therapies.
Desmoid tumors are benign, locally aggressive and irregularly shaped tumors that can cause significant deformity, morbidity and mortality resulting from local mass effects causing compression and pain, muscular contracture or obstruction of adjacent neurovascular structures. MR-HIFU ablation can be used to target specific areas within larger tumors that may be contributing most to this type of morbidity. The resultant ablation zone can be visualized as a volume of non-perfused and non-enhancing tissue on contrast enhanced MRI imaging. Measuring total tumor, perfused and non-perfused volumes using volumetric analysis may provide better objective measurements of tumor response to MR-HIFU local therapy compared to unidimensional measurements.
Methods: This is a retrospective review of MRI images from 9 patients with histologically diagnosed recurrent, refractory and symptomatic desmoid tumors from Children’s National Medical Center (CNMC) and Cincinnati Children’s Hospital Medical Center (CCHMC). All patients were treated with MR-HIFU on a clinical trial or compassionate use protocol. Unidimensional measurements were performed using digital calipers on Synapse workstation and Osirix workstation for patients from CNMC and CCHMC, respectively. Volumetric analysis was performed using Osirix software. Total tumor volume (TTV) was segmented and calculated by outlining the tumor in all axial planes on post-contrast T1-weighted images. Non-perfused volume (NPV) was similarly measured on axial planes using subtraction images that were generated from pre- and post-contrast T1-weighted images. Perfused tumor volume (PTV) was measured as the subtraction of NPV from TTV.
Results: Nine patients (median age 15.3 years, range 6-23 years; 4 males) underwent treatment (tx) with MR-HIFU (n=3, 1 tx; n=5, 2 tx; n=1, 3 tx). Tumors were axial (n=3) or located in the lower extremities (n=6). The median pretreatment TTV was 266.9 cm3 (range 19.7 – 657.2 cm3). NPV was not measurable pre-treatment and TTV equaled PTV. At one month post-treatment, the median TTV was 278.2 cm3 (range 23 – 675.7 cm3), median PTV was 214.3 cm3 and median NPV was 64 cm3. There were no objective RECIST responses immediately post treatment. Table 1 shows individual volumes for all patients. Figure 1 demonstrates volumetric analysis for patient 1 including outlined TTV (white) and NPV (red).
Conclusion: Volumetric analysis provides more detailed measurements of treatment effect including percentages of perfused and non-perfused tumor volume that is not reflected by unidimensional measurements, which may better determine treatment effects with HIFU therapy. Small increases in TTV are thought to be due to inflammation and edema post ablation treatment. These volumes are useful measurements that can be followed over time to establish how changes in TTV relate to perfused and non-perfused tumor components. Analysis of subsequent imaging at later follow up periods, as well as following retreatment, is ongoing and will be included at time of presentation.
 
Poster #013 3254342
TWO WEEKS INTERVAL OF METHOTREXATE AND VINBLASTION CHEMOTHERAPY SHOWS THE SIMILAR EFFECT AS WEEKLY ADMINISTRATION
Yoshihiro Nishida, MD, PhD1; Tomohisa Sakai2; Hiroshi Koike2; Hiroshi Urakawa2; Eisuke Arai2;
Kunihiro Ikuta2; Yuichi Ando3; Koki Shimizu4; Naoki Ishiguro2
1Rehabilitation, Orthopaedic surgery, Nagoya University Hospital, Nagoya, Aichi, Japan; 2Orthopaedic Surgery,
Nagoya University Graduate School and School of Medicine, Nagoya, Aichi, Japan; 3Medical Oncology, Nagoya
University Graduate School and School of Medicine, Nagoya, Japan; 4Orthopaedic Surgery, Tonokosei Hospital,
Mizunami, Japan
Objective: Several studies have shown efficacy of low-dose chemotherapy with methotrexate (MTX) and vinblastine (VBL) for desmoid-type fibromatosis (DF). Many regimens in these studies used a weekly dosing regimen to demonstrate their effectiveness. Since 2003, meloxicam, which is a selective COX-2 inhibitor, has been administered consecutively and prospectively, as a first line treatment. We have used MTX + VBL chemotherapy in a regimen of once every two weeks, which was different from that used in previous reports, for refractory patients. The aim of this study was to reveal the clinical outcome of low-dose chemotherapy with MTX+VBL in a regimen of once every two weeks, additionally to determine the useful factors to predict the efficacy of this chemotherapy including CTNNB1 mutation status.
Methods: Since 2003, 167 cases were histologically diagnosed as DF. Among them, 36 cases were treated with MTX (30mg/M2) +VBL (6mg/M2) chemotherapy. Treatment interval was basically 2 weeks according to our previous study. However, the dosing interval was extended to once every 3-4 weeks depending on the patient’s side effects and preference, and tumor reduction effects. Effectiveness was evaluated with MRI and/or CT every 3 months according to Response Evaluation Criteria in Solid Tumors (RECIST). Frozen or FFPE (Formalin-Fixed Paraffin-Embedded) specimens obtained at biopsy or previous surgery were subjected to the analyses for CTNNB1 mutation status by Sanger method. Clinical outcome with this 2-weeks interval regimen was investigated, and factors correlating with the efficacy were analyzed.
Results: Male was 13, female was 23 cases, mean age at the treatment was 36±18 years. Mean maximum diameter of tumor was 15±18 cm. Twenty-nine cases (81%) had CTNNB1 or APC mutation. Mean treatment duration and cycles of MTX+VBL were 20 months and 29 cycles, respectively. According to RECIST, PD in 2, PR 1n 15, and SD in 19. Response rate (PR) was 42%, and clinical benefit rate (PR+SD) was 94%. It took an average of 10 months to show a response in PR cases. According to CTCAE, Grade 3 or more adverse events were observed in only one case (2.8%) As factors relating to the response rate, CTNNB1 mutation status, gender, age, size, and location did not affect the outcome with RECIST evaluation. Longer treatment duration and cycles of chemotherapy were significantly associated with the outcome (P=0.003 and 0.005, respectively). In 15 cases of PR, recurrent tumors significantly took longer time to get efficacy (P=0.027), and tumors arising in trunk and extremities tended to take longer time (P=0.1).
Conclusion: Every 2-weeks’ regimen showed 42% of response rate, which was similar to those (40-52%) reported in previous studies (every week regimen). Rate of grade 3-4 toxicity was 2.8% in our study, which was lower than those (13-40%) reported in previous studies (every week’s regimen). On the other hand, time to response in the present study was 10 months (mean), which was longer than that (6 months, mean) reported with every week’s regimen.
Low-dose MTX+VBL chemotherapy with 2-weeks’ regimen is effective treatment for refractory DF regardless of various clinical factors and CTNNB1 mutation status. It will take time to obtain objective response.
 
Poster #018 3255781
DEVELOPMENT OF MULTIFOCAL EXTRA-ABDOMINAL DESMOID FIBROMATOSIS AFTER SURGICAL RESECTION
Brendon Bauer; Nadine L. Williams; Stephen Morris; Alex Mierke; Omar Ramos; Lee M. Zuckerman
Orthopaedic Surgery, Loma Linda University Medical Center, Loma Linda, CA, USA
Objective: Multifocal extra-abdominal desmoid fibromatosis is a rare entity. Both sporadic and hereditary entities have been described. Trauma has been described as a possible etiology of sporadic fibromatosis. We report on two cases of solitary, sporadic fibromatosis that developed multifocal disease after surgery.
Methods: The cases of a 21-year-old female with fibromatosis involving the right hemipelvis (Figure 1) and a 20-year-old male with involvement of the right ankle (Figure 2a) were reviewed. Both patients had a negative evaluation for Gardner syndrome including a colonoscopy. Biopsy was performed on two separate tumors that developed after surgery to confirm multifocal disease.
Results: Both patients developed distant multifocal disease in the extremity affected by the surgery. Neither patient had multifocal disease prior to their last surgery. The 21-year-old female underwent a single surgery with resection of the primary tumor including ligation and en bloc resection of the femoral vein and lymphatics. She developed significant lymphedema post-operatively. Five years after surgery she was found to have multiple tumors in her right leg below the knee (Figure 3). The 20-year-old male presented after multiple resections at an outside institution with local recurrence and fungation of the tumor. Multiple procedures were performed in order to attempt limb-salvage surgery. The patient elected to proceed with a below the knee amputation after multiple recurrences. Post-operatively the patient developed sores and folliculitis multiple times under his prosthesis due to sweating while working. Thirty-two months after amputation, the patient developed tumors at the posterior aspect of his stump and the popliteal fossa where his prosthesis was irritating the soft tissues (Figure 2b). Both patients elected for non-surgical management and the tumors are stable 2.5 and 3 years after the diagnosis of multifocal disease. No evidence of disease outside of the affected extremity has developed.
Conclusion: Multifocal fibromatosis is rare. These two cases are felt to have developed after chronic irritation and trauma to the soft tissues due to significant lymphedema and from use of a prosthesis. Chronic inflammation and repetitive trauma may be considered a risk factor for developing multifocal disease.
 
Poster #021 3256403
COMBINATION DRUG THERAPY AND AGGRESSIVE FIBROMATOSIS
Puviindran Nadesan, BSc1; Raymond Poon2; Vijitha Puviindran1; Mushriq Al-Jazrawe4; Sean Ryan1; Alessandro Datti6; Robert Maki5; Alexander Lazar3; Benjamin Alman1
1Orthopaedic Surgery, Duke University, Durham, NC, USA; 2Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; 3MD Anderson, Houston, TX, USA; 4Broad Institute, Cambridge, ME, USA; 5Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA; 6Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada
Objective: Aggressive fibromatosis (AF), commonly referred to as Desmoid tumor, is a locally aggressive lesion. Surgery is associated with a high recurrence rate, and in recent years there has been increased interest in non-surgical management. Clinical studies are limited by small patient numbers and the need for long term follow up. As such, preclinical studies to assess possible therapies are useful in informing treatment approaches. Prior studies investigated single agent therapies through both in vivo and in vitro studies; however, there is a paucity of literature available on multi-drug regimens. A multicenter drug screen has identified numerous medications that show promising activity in AF. Therefore, we sought to investigate various combination regimens from the drug screen to determine drug synergies and the utility of multidrug therapy in AF.
Methods: Our mouse model, APC1638N, develops AF tumor that is structurally similar to human AF tumor. In this study, we chose male mice that develop around 25 tumors per mouse by the age of 6 months. The treatment was started when the mice are around 8 weeks old (2 months) and continued until sacrificed at the age of 6 months. At which, an observer who is blinded to the groups, manually counted the tumors and measured tumor volume. Mice were treated with either monotherapy or combination therapy. Drugs which were effective as single agents in initial analyses were studied in combinations. Dexamethasone (Dex), Dasatinib (Das), AV-412 tosylate (AV), FAK inhibitor 14 (FAK), IKK-16 (IKK), PF-03084014 (PF), KB-R7943 mesylate (KB), Nefopam (Nef), and Y26763 (Y267) were selected for therapy. AF tumors were also evaluated through immunohistochemistry (IHC) for markers of proliferation and apoptosis (KI67 and caspase).
Results: Gross tumor analysis from Apc+/Apc1638N mice has shown a significant decrease in tumor number with most combinations. We found that the following combinations significantly reduced tumor number or the volume in the APC1638N mice without adversely affecting the mouse: Dex + FAK, Dex + Das, Dex X Y267, Dex X AV, Dex X IKK, Das X FAK, Das X AV, Das X Y267, Das X PF, Das X KB, AV X FAK, AV X PF, AV X KB, AV X IKK, FAK X Y267, FAK X KB, FAK X IKK, IKK X PF, IKK + KB, PF + KB, KB + Nef, Y267 + Nef. IHC demonstrated increased caspase activity and decreased KI67 activity for the combination chemotherapy treatments.
Conclusion: Desmoid tumors are locally aggressive lesions and due to high local recurrence rates, there is a need for effective chemotherapeutic options. Based on the preliminary results of this study, combination therapy appears to be effective treatment options, which may warrant further evaluation with clinical trials.
 
Poster #022 3256572
CRYOABLATION FOR DESMOID TUMORS: THE FRENCH NATIONWIDE CRYODESMO-01, CURRENT PRACTICE AND PERSPECTIVES
Jen Wmmanuel Kurtz, MD, PhD9; Xavier Buy1; Erik Sauleau8; Maud Toulmonde2; Frédéric Deschamps3; Charles Honoré4; Amine Bouhamama5; Jean-Yves Blay6; Afshin Gangi7
1Interventional Radiology, Institut Bergonié, Bordeaux, France; 2Medical Oncology, Institut Bergonié, Bordeaux, France; 3Interventional Radiology, Institut Gustave Roussy, Villejuif, France; 4Surgery, Institut Gustave Roussy, Villejuif, France; 5Interventional radiology, Centre Léon Bérard, Lyon, France; 6Medical Oncology, Centre Léon Bérard, Lyon, France;
7Interventional radiology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 8Statistics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 9Medical Oncology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Objective: Desmoid tumors (DT) are rare tumors (2-4 cases/million/year) that originate from musculoaponeurotic structures, and related so APC or beta-catenin gene alterations. Cryoablation is a promising interventional radiology technique that is suitable for DTpts. The procedure is based on repeated cycles of freezing/passive thawing of the tumor, leading to cell death. CRYODESMO-01 was a nationwide phase II study assessing cryoablation in advanced DT. Retrospective data for cryoablation in expert centers with long-term follow up are also available in patients treated before CRYODESMO, and provide useful data for further developement of the technique.
Methods: CRYODESMO-01 was the first prospective, open-label, non-randomized, non- comparative, multicentric pilot study assessing cryoablation in non-abdominopelvic DT pts progressing after two lines of treatment. The study was funded by the French National Cancer Institute and supported by the French Sarcoma Group and the SOS Desmoid pts advocacy group.The primary endpoint was the rate of non-progression at 12 months; secondary endpoints included safety, time to disease progression (TDP), quality of life (QoL), assessment of pain and functional status. Inclusion criteria were: pts 18 y.o., confirmed DT deemed accessible by the cryoablation operator , progressive disease after at least two lines of adequate medical therapy or with functional symptoms/pain, adequate biological parameters, informed consent and affiliation to social security. Data from CRYODESMO will be compared to a series of patients treated in an expert center to provide longer follow-uo experience and additional data, to support further development of cryoblation.
Results: 50 pts were enrolled from in 4 centers (78% female). The mean age was 41 y.o (range 19-73). Tumor location included limbs (36%); trunk (60%) and cervical area (4%). The median tumor volume was 111cm3(range 0.6-1 068). The rate of non-progressing disease +12 months was 86% (CI95% 73%-94%). Grade 1 and 2 toxicity occured in 32.8 and 44.5% of cases, whereas 11 pts (22%) had grade 3 and 4 AEs, all with a favorable outcome. Overall, 63% and 83% of pts experienced an improvement in functional status (better utility) and pain scores, respectively. Data from our expert center reinforce the feasibility of cryoablation in large tumors, as well as DT of the extermities, showing functional benefit and strong reduction of analgesics intake, suggesting that a cure might be achievable with this innovative technique.
Conclusion: Cryoablation is feasible in progressive DT pts, and has a favorable safety profile. The primary endpoint of the study was met and coupled with expert centers retrospective experiencen support the future incorporation of cryoablation. Cryoablation will soon challenge medical therapy as front-line therapy in the forthcoming randomized trial (CRYODESMO-02).
 
Poster #023 3257659
CAN WAIT AND SEE BE THE STANDARD OF CARE FOR INITIAL APPROACH TO PRIMARY SPORADIC DESMOID TUMORS? PRELIMINARY DATA FROM MULTICENTER EUROPEAN PROSPECTIVE STUDIES
Chiara Colombo1; Milea Timbergen4; Paola Boccone2; Dirk Grunhagen4; Erica Palesandro2; Marco Fiore1; Alba Bianco1; Federica Perrone1; Elena Palassini1; Lorenzo D’Ambrosio2; Silvia Stacchiotti1; Paola Collini1; Angelo Paolo Dei Tos3;
Paolo Casali1; Giovanni Grignani2; Alessandro Gronchi1; Cornelis Verhoef4
1Fondazione IRCCS Istituto Tumori Milano, Milan, Italy; 2IRCCS Istituto Candiolo, Candiolo, Italy; 3Ospedale di Treviso, Treviso, Italy; 4Erasmus MC Cancer Institute, Rotterdam, Netherlands
Objective: In recent years, retrospective evidence of long term disease stabilization and spontaneous regression of sporadic desmoid tumor (SDT) has been provided. As a result, a frontline wait and see approach (W&S) has been more routinely proposed. CTNNB1 coding for β-catenin is mutated in more than 90% of patients. Furthermore, a specific mutation (45F) was found to be correlated with a worse post-surgical outcome. However, the prognostic role of β-catenin mutations is not fully understood and has never been explored in patients under W&S before any active therapy is performed. The main objective of this study was to prospectively evaluate the role of W&S in patients with primary SDT and to correlate β-catenin mutational status with the clinical outcome.
Methods: This study comes from the combination of 2 prospective European multicenter (Italian and Deutch centers) observational studies aimed at evaluating the progression rate in patients affected by primary SDT managed with a front-line conservative approach (W&S). β- catenin mutational status was analyzed.
Inclusion criteria were:
-Pathological diagnosis of SDT
-Primary disease at diagnosis or incompletely resected residual disease (R2 resection)
-Histological diagnosis confirmed by expert sarcoma pathologists according to the WHO criteria
-Measurable disease evaluated by on contrast-enhanced MRI (ce-MRI) T1 and T2 weighted images or contrast enhanced CT scan (for intra-abdominal location) or ultrasound
Patient and tumor-related factors, treatment variables, follow up findings, time to progression and status at last follow-up were recorded. Follow-up (FU) schedules were identical in the 2 studies and required clinical evaluation and ce-MRI (or CT scan or ultrasound) at 3, 6, 9, 12 months, then every 6 months until the third year. Upon progression (RECIST or not), defined as tumor growth proven by imaging and/or clinical examination, active treatments were proposed according to physician’s preference and registered in the clinical database.
Results: Between 2013 and 2018 a total of 199 patients with CTNNB1 mutational status available (except one for which the analysis is pending) entered the study (81% female, 19% male); median age 39 (IQ, 33-48) years; sites distribution: abdominal wall (46%), trunk (27%), extremity (18%), intra-abdominal (3%), head/neck (6%). Median follow-up was 18 (IQ, 10-28) months. At the time of last follow up: 11/199 had spontaneous complete regression, 41/199 spontaneous partial regression, 86/199 stable disease, 61/199 progression. 31/71 patients started an active treatment for PD. The median time to an active treatment was 8 (IQ range, 5-13) months. A preliminary analysis on the correlation between β-catenin mutational status and outcome revealed that 9/26, 8/108, 2/25 and 4/39 patients with DT harboring 45F, 41A, WT or other mutations had to start an active treatment for progression, respectively. Ten patients required surgery after enrollment.
Conclusion: This study prospectively confirmed that W&S for primary SDT is safe in light of the high rate of regressions and spontaneous growth arrest. SDT have a favorable course in more than 60% of patients. A higher risk of worse outcome for patients harboring 45F was observed on the initial analysis but needs further validation on a longer FU. Upon progression, active treatments were considered on an individualized basis, while persisting in the W&S could still pay off.
 
Poster #108 3241854
DIMENSIONAL AND NON-DIMENSIONAL CHANGES WITH LOW-DOSE CHEMOTHERAPY IN SPORADIC DESMOID TUMORS (DT)
Edoardo Zanchetta1; Chiara M. Ciniselli2; Chiara Colombo3; Silvia Stacchiotti4; Giacomo Baldi4; Salvatore Provenzano4; Rossella Bertulli4; Noemi Simeone6; Alessandra Casale5; Francesca G. Greco5; Paolo Verderio2; Marco Fiore3;
Alessandro Gronchi3; Paolo Casali4; Carlo Morosi5; Elena Palassini4
1Postgraduation School in Radiodiagnostics, Università degli Studi di Milano, Milan, Italy; 2Unit of Bioinformatics and Biostatistics – Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 3Oncological Surgery Unit 4, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 4Medical Oncology Unit 2, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 5Diagnostic and Interventional Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 6Postgraduation School in Medical Oncology, Università degli Studi di Milano, Milan, Italy
Objective: A number of medical therapies were shown to be active in DT, including low-dose methotrexate (MTX) plus vinca alkaloids. Considering that RECIST criteria may underestimate chemotherapy activity, we herein report on the results of a retrospective study investigating changes in volume and MRI T2-weighted signal intensity in sporadic DT treated with low-dose MTX plus vinca alkaloids.
Methods: We retrospectively reviewed all cases of sporadic DT treated with low-dose weekly MTX plus vinca alkaloids at our institution over the last 20 years, evaluated by Magnetic Resonance Imaging (MRI). Chemotherapy was administered weekly until reaching a number of cycles between 40 and 50 or until reaching one year of treatment. MRI at baseline, at 6 and 12 months from start of chemotherapy, at the end of treatment and during follow-up were analyzed. A manual segmentation of the lesions in a slice-by-slice fashion was performed using IntelliSpace Portal Tumor Tracking software (Philips); diameters, volume and mean T2 signal intensity of the lesions (which was then normalized to the intensity of the muscle) were obtained. Descriptive statistics and graphical representation were implemented.
Results: We identified 27 sporadic DT patients eligible for the study. There were 23 females (85%) and 4 males (15%). The median age was 39,8 years (range 18,1-68,4 years). Tumor site was: extremities/girdles, abdominal wall, thoracic wall, neck and intra-abdominal in 11 (41%), 7 (26%), 4 (15%), 3 (11%) and 2 (7%) patients, respectively. All patients were progressing before starting chemotherapy. The median duration of chemotherapy was 13,9 months (range 3,5-18,5 months) for a median number of cycles of 40 (range 12-63). Reasons for chemotherapy discontinuation were treatment completion in 26 patients (96%) and progressive disease according to RECIST in 1 case (4%). According to RECIST criteria, best response was: partial response (PR) in 7 patients (26%), stable disease (SD) in 18 (67%; with a minor dimensional reduction in 17 and a minor increase in 1) and progressive disease (PD) in 2 (7%). When considering tumor volume, a reduction of at least 65% (roughly equivalent to 30% decrease in one diameter as per RECIST) was achieved in 11 subjects (41%), a smaller volume decrease in 13 (48%) and a tumor volume increase in 3 (11%). Six patients (22%) had a minor decrease or even a slight increase in longest diameter while showing a tumor volume reduction greater than 65% (apparently, lesions shrank without diminishing in the main diameter). When considering normalized T2 signal intensity, a decrease of at least 50%, as best response, was observed in 14 patients (52%), a minor reduction in 9 patients (33%) and an increase in 4 patients (15%). By looking at the three parameters altogether, Figure 1 reports best responses achieved with chemotherapy for each patient. In 3 cases an important discrepancy between dimensional (mono-dimensional and volumetric) changes and T2 signal intensity changes was observed. In particular, in 2 patients T2 signal intensity increased despite a decrease in volume: in one case, clinical worsening was observed during treatment and several further treatments were administered after chemotherapy interruption; the other patient was asymptomatic and stopped treatment just one year ago. In one additional case, volume increased significantly during the first months of treatment, than a reduction was observed, while T2 signal intensity decreased; the patient stopped treatment 3 years ago and is asymptomatic.
Conclusion: In this series of DT treated with low-dose chemotherapy, dimensional reductions were observed in the vast majority of patients, even if RECIST partial responses were achieved in a relatively small number. Normalized T2 signal intensity changes may be more informative, especially when diverging from dimensional variations. An effort to better understand correlations between dimensional changes, T2 signal intensity changes and clinical outcome is ongoing.
 
Poster #133 3252978
CTNNB1 MUTATIONS AND AGGRESSIVE BEHAVIOR IN NEUROMUSCULAR CHORISTOMA-ASSOCIATED FIBROMATOSIS
Jodi M. Carter, MD, PhD; Andres Maldonado; Matthew Howe; Robert J. Spinner
Mayo Clinic, Rochester, MN, USA
Objective: Neuromuscular choristoma (NMC) is a rare, developmental malformation that typically arises in the major proximal peripheral nerves, most commonly the sciatic nerve. NMC is strongly associated with development of a peri-lesional desmoid-type fibromatosis (DTF). Previously, we reported that activating CTNNB1 mutations occur in NMC and NMC-fibromatosis, similar to those seen in sporadic DTF. As CTNNB1 mutational subtypes have established prognostic and predictive significance in sporadic DTF, we evaluated the frequency of CTNNB1 mutational subtypes and the clinical outcomes in a series of patients with NMC-fibromatosis.
Methods: With institutional approval, cases coded as neuromuscular choristoma and desmoid-type fibromatosis, with available formalin-fixed, paraffin-embedded (FFPE) tissue were retrieved. Clinical data, radiologic images and pathologic material were reviewed. Archival FFPE tissues, enriched for NMC-fibromatosis, were macro-dissected. Genomic DNA was extracted using the QIAamp® DNA FFPE Tissue kit (QIAGEN, Valencia, CA) and amplified by polymerase chain reaction using primers specific for the region surrounding CTNNB1 codons 41 and 45, followed by pyrosequencing and mutation analysis.
Results: Seven cases of biopsy-proven NMC-fibromatosis, occurred in 3 females and 4 males (median age at diagnosis: 14 y, range 5 to 51y) with biopsy-proven (N=5) or radiologic diagnosis (N=2) of NMC of the sciatic nerve. In all cases, NMC-fibromatosis arose within the affected nerve territory: involving the soft tissues of the buttock, posterior thigh or popliteal fossa, and cases developed following NMC biopsy (N=5) or spontaneously (N=2). All 7 NMC-fibromatosis contained CTNNB1 mutations, including 5 p.S45F, 1 p.S45P and 1 p. T41A. In 6 cases with clinical follow-up (mean 3.5 y; range 1-8y), all patients had disease progression, irrespective of initial treatment modality: surgical resection (N=3) cryoablation (N=1), tamoxifen (N=1) or observation (N=1). One patient developed multifocal, metachronous NMC-fibromatosis at spatially-distinct sites along the NMC-affected nerve. Disease stabilization was achieved with adjuvant radiation therapy (N=3), doxorubicin-based chemotherapy (N=1) or receptor tyrosine kinase inhibitor-based therapy (e.g. sorafenib) (N=1).
Conclusion: NMC-fibromatosis frequently harbors CTNNB1 p.S45X mutations and displays aggressive biologic behavior, requiring adjuvant local or systemic therapy for disease stabilization. As such, and as development of NMC-fibromatosis is frequently precipitated by iatrogenic injury (i.e. biopsy) of the NMC, we now employ a “no-touch” approach for the diagnosis of NMC, and rely on clinical and MR imaging features for both diagnosis and surveillance whenever possible.
 
Poster #151 3219544
IN SITU CRYO-ABLATION OF DESMOID TUMORS ASSISTED BY 3D MODELLING AND NAVIGATION BY O ARM
Ortal Segal; Ido Druckmann; Yehuda Kollander; Solomon Dadia; Amir Sternheim; Yair Gortzak
The National Unit for Orthopedic Oncology, Tel Aviv Medical Center, Tel Aviv, Israel
Objective: Aggressive fibromatosis, is a rare, locally invasive, non-metastasizing condition. The natural history of desmoid tumors is variable and includes periods of indolence, growth, and regression.
Reasons for treatment and how? Volumetric progression, Symptoms worsening & Cosmetic disturbance.
Large en-bloc surgery is no longer regarded as the cornerstone treatment. Rate of relapse after surgery exceeds 60% in larger series. Shift to a more conservative approach, the ‘wait-and-see’ policy was adopted during last years.
Other forms of treatment include: radiation, systemic therapy, and neoadjuvant radiation with or without chemotherapy. neither approach has emerged as optimal or definitive, and each is associated with high recurrence rates or complications from the treatment itself.
In situ cryotherapy is a minimal invasive procedure that can decrease tumor size by apoptosis. cryotherapy is a safe procedure the does not damage collagenous structures surrounding the tumor. During the procedure, the ice ball in the tumor can be monitored using imaging studies such as CT or ultrasonography. The proper position and the number of needles is crucial in order to ideally cover and surround the tumor mass. By 3D modelling and planning this goal can be achieved. The most effective trajectory can be determined and vital organs (nerves, blood vessels and other structures) can be protected. Using the O arm navigated system, real time positioning and monitoring is possible.
Methods: 11 patients with histolocally confirmed extra abdominal desmoid tumor with progression of tumor mass on imaging and severe functional disturbance were treated with in situ cryosurgery. All patients were scanned by MRI and CT prior the procedure. Segmentation of the tumor and surrounding structures was perform into 3D surface models. Then by extrapolating the “kill zone” of each cryotherapy needle we placed the needle in to the tumor. All procedures took place at the operating theater under general anesthesia. According to previous planning, several isolated cryo needles (Galil medical ice-rod plus, Israel) were inserted into the tumor mass under O arm navigated guidance. Then cryotherapy protocol was activated which includes 10 minutes freezing, 5 minutes active thawing and repeated 10 minutes freezing. During freezing cycles, a scan by the O arm was done in order to monitor the “ice ball” in the tumor.
Results: 10 tumors progression has stopped. 2 patients underwent repeated ablation do to relative tumor growth. in 6 patients (54.5%) – there was average of 53% reduction in tumor volume within 6 months. In 2 patients the tumor disappeared completely. In 3 patients the tumor as stopped growing but no reduction was noted. One patient the tumor is growing (close to brachial plexus) and One patient data collection is missing (Russia). Quality of life – SF 36 – physical health, emotional health and pain was significantly improved.
Conclusion: In situ cryo-surgery in a safe procedure and effective in stabilizing tumor mass in desmoid tumors. In 90% of the patients we were able to stop tumor growth and improve quality of life. By 3D modelling correct positioning of cryo needles can be optimal and safer for the patients.
 
Poster #183 3223161
THERAPEUTIC VALUES OF RADIOTHERAPY IN THE TREATMENT OF DESMOID TUMORS
Yoo-Kang Kwak, MD, PhD1; Chul Seung Kay1; Yeon Sil Kim2; So Jung Lee1; Ji Hyun Hong1; Eun Young Park2
1Radiation Oncology, Incheon St. Mary’s Hospital, Incheon, Korea (the Republic of);
2Radiation Oncology, Seoul St. Mary’s Hospital, Seoul, Korea (the Republic of)
Objective: Desmoid tumors are rare non-malignant tumors and account for less than 3 percent of all soft tissue tumors. The disease, also known as aggressive fibromatosis, do not metastasize or dedifferentiate, but are locally aggressive tumors that can recur. The optimal treatment of the disease is not yet established. The aim of this study was to examine the outcome of radiotherapy in desmoid tumors and identify the therapeutic value of radiotherapy in the treatment of desmoid tumors.
Methods: Patients diagnosed with desmoid tumors and treated with radiotherapy between January, 2000 and December, 2018 were included. Twenty-two patients’ data were retrospectively analyzed. Two patients had Gardner’s syndrome. Fourteen patients (63.6%) were treated with radiotherapy after recurrence and eight (36.4%) patients were treated at first diagnosis. Seventeen patients (77.3%) were treated postoperatively, while five patients (22.7%) were treated radically. Radiotherapy target was created with 1.5 – 3 cm added to gross tumor or operative tumor bed. Median radiotherapy dose was 55.8 Gy, delivered with 1.8 – 2.3 Gy per fraction.
Results: Median follow up time was 35.1 months (range, 1.5 – 234.8 months). Twenty-one patients were assessed for recurrence since one patient was loss to follow up. Among them, four patients (18.2%) recurred after radiotherapy. Three local failures were classified as in-field failure while one was marginal failure. None of the failures occurred totally out-of-field. Time to local recurrence after radiotherapy ranged from 2.5 – 180.4 months. Except for the patient with 2.5 months follow up, others were treated with additional excision. One patient who recurred again after re-excision had underlying Gardner’s syndrome. In postoperative cases, patients treated with more than 55.8 Gy and with clear resection margin had better recurrence free survival, although the difference did not reach statistical significance.
Conclusion: Role of radiation therapy in desmoid tumors is of value since local control rate was satisfactory. Resection margin status and postoperative radiotherapy dose might be crucial when considering radiotherapy in the treatment of desmoid tumors.

2018 DTRF Patient Meeting Presentations

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2018 DTRF Research Workshop Presentations

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Miscellaneous

Childhood Soft Tissue Sarcoma Treatment (PDQ®)- Patient version

This PDQ cancer information summary has current information about the treatment of childhood soft tissue sarcoma. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Childhood Soft Tissue Sarcoma Treatment (PDQ®)- Health Professional version

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood soft tissue sarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

2018 ASCO Annual Meeting

Presentations

“Desmoid Tumors Biology: Exploiting Estrogen and Notch Signaling”, Sandra P. D’Angelo, MD, Assistant Attending, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center.

“DESMOPAZ pazopanib (PZ) versus IV methotrexate/vinblastine (MV) in adult patients with progressive desmoid tumors (DT).” A randomized phase II study from the French Sarcoma Group.

Maud TOULMONDE, Isabelle RAY-COQUARD, Marina PULIDO, Thierry ANDRE, Christine CHEVREAU, Nicolas PENEL, Emmanuelle BOMPAS, Antoine THYSS, François BERTUCCI, Celeste LEBBE, Axel LE CESNE, Patrick SOULIE, Sophie PIPERNO-NEUMANN, Fabiola CECCHI, Todd HEMBROUGH, Florent PETITPREZ, Carine BELLERA, Julien ADAM, Jean-Yves BLAY, Antoine ITALIANO

 

Posters

1. Vincenzi¹*, S. Provenzano2, A. Brunello3, G. Badalamenti4, M. Nannini5, T. Ibrahim6, P. Hohenberger7, S. Gasperoni8, A. Napolitano¹, M. Silletta¹, M. Vitellaro2, A.P. Dei Tos9, D. Santini¹, G. Tonini¹ and E. Palassini2

1. Campus Bio-Medico, Rome; 2. Istituto Nazionale Tumori, Milan; 3. Istituto Oncologico Veneto, Padua; 4. University of Palermo, Palermo; 5. University of Bologna, Bologna; 6. Istituto Oncologico Romagnolo, Forlì;

University Hospital Mannheim, Mannheim; 8. Istituto Toscano Tumori, Firenze; 9. General Hospital of Treviso, Treviso

“FAP-Related Desmoid Tumors Treated with Low-Dose Chemotherapy.”

2018 CTOS Annual Meeting

Presentations

“Can wait and see be the standard of care for initial approach to primary sporadic desmoid tumors? Preliminary data from an Italian Sarcoma Group prospective study.”

Chiara Colombo1; Marco Fiore1; Tiziana Venesio2; Erica Palesandro2; Paola Boccone2; Lorenzo D’Ambrosio2; Alba Bianco1; Paola Collini1; Elena Palassini1; Silvia Stacchiotti1; Angelo Paolo Dei Tos3; Paolo Casali1; Federica Perrone1; Alessandro Gronchi1
1Fondazione IRCCS Istituto Tumori Milano, Milan, Italy; 2IRCCS Istituto Candiolo, Torino, Italy; 3Ospedale di Treviso, Treviso, Italy

2017 DTRF Patient Meeting Presentations

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2017 DTRF Research Workshop Presentations

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2017 CTOS Meeting Abstracts and Posters

PAPERS

 

Prognosis of desmoid tumours initially managed with surveillance only at all anatomical locations   

Winan J. van Houdt, MD, PhD, MSc1; Alisha Patel1; Robin L. Jones2; Myles J. Smith1; Aisha Miah3; Charlotte Benson2; Shane Zaidi; Christina Messiou4; Eleanor Moskovic4; Dirk C. Strauss1; Andrew J. Hayes1; Olga Husson2; Winette van der Graaf2

1 Department of Surgical Oncology, The Royal Marsden Hospital, London, United Kingdom; 2 Department of Medical Oncology, the Royal Marsden Hospital, London, United Kingdom; 3 Department of Clinical

Oncology, the Royal Marsden Hospital, London, United Kingdom; 4 Department of Radiology, the Royal Marsden Hospital, London, United Kingdom

 

An update on the management of sporadic desmoid-type fibromatosis: A European consensus initiative between Sarcoma Patients Euronet (SPAEN) and European Organisation for Research and Treatment of Cancer (EORTC)/ Soft Tissue and Bone Sarcoma Group (STBSG)

Bernd Kasper, MD, PhD1; Christina Baumgarten2; Jesica Garcia2; Sylvie Bonvalot3; Rick Haas, MD, PhD4;

Florian Haller5; Peter Hohenberger1; Nicolas Penel6; Christina Messiou7; Winette van der Graaf8; Alessandro Gronchi9

1 Interdisciplinary Tumor Center, Mannheim University Medical Center, Mannheim, Germany; 2 Sarcoma Patients EuroNet (SPAEN), Wölfersheim, Germany; 3 Department of Surgical Oncology, Institut Curie, PSL University, Paris, France; 4 Department of Radiotherapy, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; 5 Institute of Pathology, Friedrich Alexander University Erlangen, Erlangen, Germany; 6

Department of Medical Oncology, Centre Oscar Lambret, Lille, France; 7 Radiology, The Royal Marsden Hospital, London, United Kingdom; 8 Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom; 9 Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

 

Autophagy inibition overcomes sorafenib resistance in CTNNB1 mutant S45F desmoid tumors

Danielle Braggio, PhD1; David Koller2; Feng Jin3; Nanda Siva4; Abeba Zewdu1; Gonzalo Lopez; Kara Batte1; Lucia Casadei, PhD1; Meng Welliver3; Anne Strohecker1; Raphael Pollock2; Dina Lev5

1 Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; 2 Department of Surgery, The Ohio State University, Columbus, OH, USA; 3 Radiation Oncology Department, The Ohio State University, Columbus, OH, USA; 4 Department of Chemical and Biomedical Engineering, West Virginia University Statler College of Engineering and Mineral Resources, Morgantown, WV, USA; 5 Surgery B’Sheba Medical Center, Tel Aviv, Israel

 

 

POSTERS

IDENTIFICATION OF NOVEL SURFACE MARKERS FOR TUMOR-STROMA INTERACTION STUDIES IN DESMOID TUMORS

Mushriq Al-Jazrawe, Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, CANADA; Q. Wei, S. Xu, J. Loree, R. Poon, Developmental & Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, CANADA; B. Alman, Duke University, Durham, North Carolina, USA

Objective: The role of stromal fibroblasts in promoting tumor growth and invasion has been underexplored in soft tissue sarcoma partly due to lack of reliable markers that differentiate between the neoplastic and non-neoplastic mesenchymal cells. Desmoid tumors (DT), characterized by proliferating and locally invasive fibroblastic cells, are driven by mutations that increase beta-catenin (CTNNB1) levels. We aimed to identify surface markers that can distinguish between the neoplastic and non-neoplastic fibroblastic cells within DT and investigate the tumor-stroma interactions that maintain the neoplastic phenotype.Methods: Multiple single cell expansions were established from each DT sample. CTNNB1 mutation status of each colony was identified by Sanger sequencing. Mutant and non-mutant colonies were analyzed by flow cytometry for the expression of 368 surface proteins. Candidate surface markers were validated by fluorescence-activated cell sorting (FACS) and double immunofluorescence. Differential secretome analysis was conducted by antibody arrays and by gene expression profiling. Transwell permeable supports were utilized for mutant-stromal fibroblast co-cultures in cell interaction studies.Results: We detected both mutant and non-mutant colonies derived from primary DT cultures. The mutant colonies expressed CD142 and CD252 while the non-mutant colonies expressed podoplanin (PDPN). FACS using these surface markers identified the mutant subpopulation in heterogeneous DT samples, including specimens that previously appeared as “wildtype.” In DT tissues, CD142 and CD252 expressing cells correlated with higher CTNNB1 staining and exhibited a distinct spatial distribution compared to PDPN expressing cells. Our secretome profiling revealed several candidate soluble factors for autocrine or paracrine signaling. CTHRC1 is one of the secreted proteins highly produced by the mutant population. Treatment with recombinant CTHRC1 increased cell proliferation while treatment with a CTHRC1 neutralizing antibody decreased proliferation.Conclusion: We have identified novel surface markers that can be utilized to rapidly and sensitively detect the mutant population within DT samples. Isolation of the mutant and non-mutant subpopulations allows for the detection of secreted factors that may be involved in tumor-stroma communication, which can be targeted therapeutically. The differential expression of these surface proteins and secreted factors suggests that they may also be used as clinical biomarkers.

COMBINATION CHEMOTHERAPY FOR AGGRESSIVE FIBROMATOSIS: PRELIMINARY RESULTS FROM BETA-CATENIN INHIBITOR, DEXAMETHASONE, AND FOCAL ADHESION KINASE INHIBITOR

Sean Ryan, Orthopaedics, Duke University Hospital, Durham, North Carolina, USA

V. Puviindran, P. Nadesan, Y. Kwak, B. Alman, Orthopaedics, Duke University Hospital, Durham, North Carolina, USA

Objective: Aggressive fibromatosis (AF), commonly referred to as Desmoid tumor, is a locally aggressive lesion often treated with surgical resection, however, high local recurrence rates generate continued interest in chemotherapeutic options. Prior authors have investigated different therapies through both in vivo and in vitro studies with variable results; however, there is a paucity of literature available on multi-drug regimens. Given the infrequent occurrence of these aggressive lesions and lack of funding to generate novel chemotherapeutics, the majority of research focuses on using current FDA approved medications in hopes for a therapeutic response in AF. At the investigating institution, a prior drug screen has returned numerous medications that show promising activity in AF. Therefore, we sought to investigate various regimens from the drug screen to determine the utility of combination therapy in AF.Methods: Apc+/Apc1638N mice, which develop AF lesions, were treated with either monotherapy or dual therapy with BC2059 (a beta catenin inhibitor), Focal Adhesion Kinase (FAK) inhibitor, and Dexamethasone. The mice were sacrificed at 6 months following treatment and tumor number and volume analyzed. AF tumors were then analyzed through immunohistochemistry (IHC), western blot, and real time PCR for markers of proliferation and apoptosis (KI67 and caspase), as well as beta catenin and downstream protein activity. Human cell cultures undergoing the same treatment combinations were then performed. Funding for this study was provided by the Desmoid Tumor Research Foundation.Results: Preliminary results from gross tumor analysis from Apc+/Apc1638N mice has shown significant decrease in tumor number with BC2059 mono-therapy compared to control (p=0.0004). Mon-therapy with FAK inhibitor and Dexamethasone trended toward diminished tumor burden, however, these results were not significant. Combination therapy with BC2059 and dexamethasone, as well as FAK inhibitor and dexamethasone showed significant decreased tumor number compared to control (p<0.0001) [figure 1]. Average tumor volume showed a similar response to treatment with combination therapy, with dual treatment outperforming control and monotherapy. These differences, however, were not significant [figure 2]. Protein, RNA, and human cell culture treatment analysis are currently being performed.Conclusion: Desmoid tumors are locally aggressive lesions, and due to high local recurrence rates, there is a need for effective chemotherapeutic options. Based on the preliminary results of this study, combination therapy with FAK inhibitors, Dexamethasone, and BC2059 (a beta catenin inhibitor) appear to be effective treatment options, which may warrant further evaluation with phase II clinical trials. Further analysis on these tumors will provide more insight into the therapeutic effects of these medications.

METHOTREXATE PLUS VINORELBINE (MTX/VBL) CHEMOTHERAPY FOR THE MEDICAL MANAGEMENT OF DESMOID FIBROMATOSIS (DF) 

Sally Burtenshaw, R. Gladdy, A.M. Olteanu, Mount Sinai Hospital, Toronto, Ontario, CANADA; S. Thipphavong, L. White, Radiology, Princess Margaret Cancer Center, Torongo, Ontario, CANADA; A.A. Gupta, P. Bradbury, A. Razak, M. Blackstein, Medical Oncology, Princess Margaret Cancer Center, Toronto, Ontario, CANADA

Objective: Objective: DF are locally aggressive benign neoplasms that can occur sporadically, in association with familial adenomatous polyposis (FAP), as a result of injury or recent pregnancy. Optimal management of these benign tumors remains controversial. MTX/VBL is systemic therapy which is not associated with any long term sequelae. To date, reports of MTX/VBL have often included patients who have failed prior radiation therapy (RT) or other systemic therapy (ie. doxorubicin). We report our experience in management of patients with progressive DF with MTX/VBL, most of whom are treatment naive.Methods: Methods: Consecutive patients with DF treated between Jan 1994 and Dec 2015 were reviewed. Treatment: MTX 25 mg/m2 IV + VBL 25 mg/m2 IV d1,8,15 q28 d for a planned max duration of 24 cycles. Data including demographics, treatment details and toxicity were collected. A radiologist re-reviewed all available MRI scans to evaluate response by RECIST and T2 changes. PFS was estimated using KM.Results: Median age of 48 patients was 33 yrs (range 13-73). Thirty seven (77%) patients were treatment nave and 11 (23%) had residual/recurrent disease. Tumour location was as follows: 16 (33%) extremity, 13 (27%) abdominal wall, 4 (8%) head and neck, 6 (13%) chest wall/back, 7 (15%) mesenteric. Two patients (4%) had multifocal DF at two sites: abdominal wall and mesentery. Prior therapy in the 11 patients included: 6 (55%) surgery alone, 2 (18%) surgery and tamoxifen, 1(9%) surgery and RT, 1 (9%) tamoxifen alone and 1 (9%) tamoxifen and Doxorubicin. Median number of cycles of chemotherapy was 19 mos (range 1 to 27; Figure 1). Schedule modification occurred in 5 patients. The majority of patients (n=27, 56%) had 18 or more cycles of therapy; 9 completed 24 mo. Reasons for early therapy discontinuation before 24 months were: toxicity (n=2, 4%), response achieved (n=28, 58%%), patient preference (n=8, 17%), PD (n=1, 2%). Most severe toxicity was grade 1/2 fatigue, nausea or both in 9 (18%), 12 (25%) and 4 (8%) patients, respectively. Three (6%) patients had neutropenia (grade 1/2). At end of therapy, response was: 8 (17%) SD, 19 (40%) PR, 20 (41%) CR, and 1 (2%) PD for a clinical benefit rate of 98%. Median PFS was 95 mo (range 57.6 to 132.4), and 5-year PFS was 72%. Of the 10 patients who recurred, 5 had had prior therapy. 5-year PFS was 53% in those that completed less than 18 mo compared to 93% in those that completed more than 18 mo.Conclusion: MTX/VBL is very safe and very effective in the treatment of patients with DF and should be considered as first-line therapy. Duration of therapy of at least 18 months is likely required to ensure good outcome.

A RETROSPECTIVE COMPARISON OF PAZOPANIB WITH ESTABLISHED THERAPIES FOR DESMOID TUMORS IN PEDIATRIC, ADOLESCENT AND YOUNG ADULT (AYA) PATIENTS

Laura Agresta, R. Nagarajan, S. Szabo, B. Turpin, H. Kim, J. Sorger, J. Pressey, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA

Objective: Desmoid tumors (DT) lack a reliably effective medical therapy. Surgical resection may be morbid and does not preclude recurrence. Radiation has potentially severe late effects, particularly detrimental in young patients. At our institution, we recently observed encouraging results with pazopanib therapy for DT compared with established therapies.Methods: Retrospective single-institution chart review comparing treatment outcomes in AYA and pediatric patients with DT treated with pazopanib to those treated with established therapies.Results: Six DT patients, 3-21 years with previously treated DT, received pazopanib; 33 DT patients received established therapies only. In both groups, the median age at diagnosis was 16 years, female patients comprised 50%, and most common DT site was extremity. In the pazopanib group, there were 4 patients with sporadic DTs, all with CTNNB1 mutations by next generation sequencing, and 2 FAP patients. In the comparison group, 5 sporadic DTs had CTNNB1 mutations and 1 had a somatic APC mutation. Established therapies showed few objective responses and most patients received multiple therapies as a result. Surgical resection had a 68% recurrence rate. One patient who received radiation developed a sarcoma in the radiation field. Of 8 patients who received vinblastine/methotrexate (VM), only 1 had a PR by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST), 5 had SD, 2 not evaluable. Toxicities included fever and neutropenia, peripheral neuropathy, nausea/vomiting. After VM, 5 of 8 required additional therapy. Of 7 patients who received sulindac/tamoxifen, none had objective improvement, 4 had SD, 1 had PD, 2 not evaluable. Five of 7 required additional therapy. All female patients developed ovarian cysts. In contrast, none of the patients progressed while on pazopanib. Best responses by RECIST were PR in 2 of 8 and SD in 6 of 8 tumors, and all extra-abdominal DTs demonstrated dramatically increased fibrosis on T2-weighted MR. A PR of 66% was observed in a patient who had failed multiple prior therapies. A mesenteric DT in a FAP patient also showed PR. Four of 6 patients reported substantial pain relief and improvement in function within 1 month. Pazopanib was discontinued in 1 patient after 18 months due to recurrent facial edema. All other toxicities responded to dose reduction and objective treatment effect was not sacrificed.Conclusion: In this series, pazopanib offered an effective treatment option for AYA patients with symptomatic DT.

FACTORS ASSOCIATED WITH DISEASE STABILIZATION IN DESMOID-TYPE FIBROMATOSES

Yong Sung Kim, M. Rosario, H. Kim, I. Han, Department of Orthopaedic Surgery, Seoul National University Hospital, Seoul, KOREA (THE REPUBLIC OF)

Objective: Spontaneous disease stabilization of desmoid-type fibromatosis (DF) has been demonstrated in many patients. Thus, watchful waiting approach without any front-line treatment is being offered to the patients who present with DF. To provide for the most suitable treatment for each patient, identification of factors predictive of disease stabilization is necessary. The purpose of this study was to assess the disease stabilization rate and identify predictive factors for disease stabilization.Methods: One hundred and forty-four patients with sporadic, extra-abdominal DF who were managed with front-line conservative treatment and followed for at least 2 years were reviewed. Tumors were radiologically diagnosed as stable when an unchanged or a continual decrease in tumor size by the longest diameter was successively recorded for at least 6 months with no renewed growth at final follow-up. The primary endpoint was tumor stabilization. Possible patient-, disease-, and treatment-related factors predictive of disease stabilization were examined. Kaplan-Meier method was used to estimate time to tumor stabilization, and the Log-rank test was utilized for univariate analysis. Multivariate analysis was performed using the Cox proportional hazards model.Results: One hundred sixteen (80.6%) out of 144 tumors were stable at final follow-up, with a mean time to stabilization of 17 months (range 0 to 153). Tumor stabilization rates at 1, 2, and 3 years were 59%, 72%, and 77%, respectively. On Kaplan-Meier analysis, patients <40 years (44.97.4 months vs. 7.31.5 months, p<0.001), with tumors ?5 cm (40.17.4 vs. 153.8 months, p=0.005), and with recurrence (49.28.2 vs. 9.12 months, p<0.001) were found to have significantly longer time to tumor stabilization. After multivariate Cox regression analysis, both recurrent presentation (RR=1.7, p=0.011) and younger age (RR=1.8, p=0.006) were the independent factors associated with disease stabilization. Analysis of recurrent disease showed 48 (67.6%) of the 71 recurrent tumors were stable at final follow-up, with a mean time to stabilization of 27 months (range 0 to 153). Stabilization rates for the recurrent tumors at 1, 2, and 3 years were 46%, 55%, and 62%, respectively.Conclusion: A front-line conservative treatment seems to be the optimal treatment for majority of patients who present with DF. Younger patients and those presenting with recurrence may require longer periods of initial observation with pain palliation as needed.

CLINIC AND MOLECULAR PROGNOSTIC FACTORS IN DESMOID TUMORS TREATED WITH UPFRONT SURGERY. A SPANISH GROUP FOR SARCOMA RESEARCH STUDY

Javier Martin-Broto, N. Hindi, Medical Oncology, Hospital Universitario Virgen del Rocio, Seville, SPAIN; D.S. Moura, M. Lopez, Instituto Biomedicina Sevilla-IBIS, Sevilla, SPAIN; M. Da Conceicao, Hospital U Son Espases, Palma de Mallorca, SPAIN; D. Marcilla, Anatomia Patológica, Hospital U Virgen del Rocio, Sevilla, SPAIN; S. Bagué, Pathology, Hospital Sant Pau, Barcelona, SPAIN; R. Ramos, Pathology, Hospital U Son Espases, Palma de Mallorca, SPAIN; R. Alvarez, Medical Oncology, Hospital Gregorio Marañon, Madrid, SPAIN; C. Agra, Pathology, Hospital Gregorio Marañon, Madrid, SPAIN; A. Sala, Medical Oncology, Hospital de Basurto, Bilbao, SPAIN; A. Ugalde, Pathology, Hospital de Basurto, Bilbao, SPAIN; I. Sevilla, Medical Oncology, Hospital Virgen de la Victoria, Malaga, SPAIN; L. Vicioso, Pathology, Hospital Virgen de la Victoria , Malaga, SPAIN; A. López Pousa, Medical Oncology, Hospital Sant Pau, Barcelona, SPAIN

Objective: Desmoid tumor (DT) management has a wide spectrum of therapeutic options, and even when surgery is currently not recommended for most cases, the fact is that a relevant number of patients still undergo surgery as first option. Clinical behavior is difficult to predict at individual basis, even for those completely resected DT. In sporadic DT, the prognostic role of different missense mutations in CTNNB1 gene has been inconsistent among several publications. Our aim was to analyze the potential prognostic role of genotype in a series of primary DT treated with surgery.Methods: Patients were selected from GEIS registry, IRBs and ethic committees approved the protocol including molecular tests in paraffin embedded tumor samples. KaplanMeier estimations were used for time-to-event variables and the log-rank test was used to compare groups. Tumor tissue was processed with the QIAamp FFPE Tissue Kit (Qiagen, Valencia, CA), according to manufacturers instructions. Exonic primers were used to amplify a sequence within exon 3 of CTNN1B by PCR. Bidirectional sequencing with specific primers was performed in an AB 3500 genetic analyzer, using the BigDye Terminator v3.1 kit (Applied Biosystems).Results: A subset of 320 patients that underwent upfront surgery was selected. The median age was 37 y (12-89). Primary sites were: limbs 28%, trunk wall 43% and miscellany 29%. The median of size was 6.5 cm (1-27) and the median of Karnofsky index was 90% (50-100). There were 108 (34%) recurrences with a median follow-up of 60 months. Mutations in exon 3 of CTNNB1 gene were found in 142 (88%) out of 162 available blocks, 89 (63%) in 41A, 31 (22%) in 45F, 22 (15%) in 45P and 20 wild type (12%). Patients harboring 45F showed statistically worse SLR compared with the rest of genotypes: 25.8 m (16.4- 35,2) vs not reached, (p=0.035). Patients with DT in limbs had significant worse median of RFS: 38 m (3-73) than trunk wall (149) or miscellany (107), p= 0.001. Likewise, patients with DT ? 6.5 cm had significantly worse RFS: 59 m (17-101) vs not reached (p=0.003).Conclusion: Tumor site, tumor size and type of mutation of CTNNB1 gene has prognostic impact in DT treated with upfront surgery. Genotype 45F entails worse RFS and it justifies further molecular related research in this entity.

STABILIZATION OF β-CATENIN: A POTENTIAL THERAPEUTIC TARGET FOR DESMOID TUMORS?

Danielle Braggio, A. Zewdu, G. Lopez, K. Batte, L. Casadei, A. Strohecker, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA; F. Jin, M. Welliver, Radiation Oncology Department, The Ohio State University, Columbus, Ohio, USA; D. Koller, R. Pollock, Department of Surgery, The Ohio State University, Columbus, Ohio, USA; R. Soldi, Beta Cat Pharmaceuticals. INC, Houston, Texas, USA; D. Lev, Surgery B, Sheba Medical Center, Tel Aviv, ISRAEL

Objective: To investigate the antitumor effect of a novel agent targeting beta catenin stabilization, BC2059, in desmoid tumor (DT) models.Methods: A panel of DT cell strains was exposed to increasing concentrations of BC2059 in vitro and evaluated for cell proliferation and colony formation capacity. Antitumor effects were assessed in vitro by cell cycle, apoptosis, and migration and invasion analysis. Cells treated with BC2059 were analyzed the association of ?-catenin with TBL1 by immunoprecipitation (IP) analysis. To further understand the effects of BC2059 treatment on DTs we analyzed the expression of ?-catenin pathway components in DT cell strains treated with BC2059 using real time PCR and western blotting.Results: BC2059 markedly inhibited proliferation, capacity of colony formation, migration and invasion of mutated DT cells, but had no effect on wild-type DTs. Comparison of ?-catenin mutation between the original tumor and the associated cell strain was the primary method used to differentiate desmoid tumor cell from fibroblast. Therefore, cell strains lacking detectable ?-catenin mutation (wild-type) could be comprised of primarily fibroblasts cells and not tumor cells. This is one possible explanation for the lack of effect of BC2059 on DT wild-type cell strains. The decrease in cell viability on mutated DT cells caused by BC2059 was due to apoptosis. Treatment with BC2059 led to a reduction of ?-catenin associated TBL1 in all mutated DT cells, resulting in a reduction of nuclear ?-catenin. Consequently, levels of genes that are target of b-catenin (e.g MDK, AXIN2) were found to be downregulated after BC2059 treatment.Conclusion: Our findings suggest that BC2059 has significant antitumor activity against ?-catenin mutated DTs through stabilization of b-catenin that leads to downregulation of its target genes. Thus, BC2059 may comprise an alternative strategy for the treatment of desmoid tumor patients. * This work was made possible in part by funding of Beta Cat Pharmaceuticals through the Product Development Award CP130058 from the Cancer Prevention and Research Institute of Texas (CPRIT).

INVESTIGATION OF NOVEL EX VIVO TISSUE DRUG SCREENING TO PREDICT THERAPEUTIC RESPONSE IN DESMOID TUMORS

David Koller, D. Braggio, A. Zewdu, K. Batte, L. Casadei, G. Lopez, D. Lev, R. Pollock, The Ohio State University, Columbus, Ohio, USA

Objective: To investigate ex-vivo fresh tumor sensitivity as a predictor of tumor responsiveness in desmoid tumors and compare to standard of care.Methods: Fresh DT tissue have been thinly sliced and exposed to different drugs and combinations ex-vivo and evaluated for viability. The expression and activation of downstream markers were analyzed in DT ex-vivo tissue slice culture by western blot.Results: Ex-vivo tissue culture is used to test tissue responsiveness to chemotherapeutic options in DT fresh tissue. Confirmation of appropriate downstream protein inhibition through western blot shows appropriate targeting and modality of cell death.Conclusion: Ex-vivo tissue culture drug testing exhibits significant predictive effects on DT tissue with appropriate downstream effect in patient specific manner compared to in-vivo data. This data suggests that ex-vivo fresh tissue drug testing may be an appropriate drug selection technique in addition to pathology and genomic data in predicting adjuvant and salvage therapy after surgical treatment. This data suggest that quick and easy personalized treatments can be tested and selected through ex-vivo culture and testing to allow optimal treatment selection. Furthermore, our results suggest that along with previous therapies, novel treatment can be tested as well.

TUMOR REDUCTION AND SYMPTOM RELIEF AFTER ELECTROCHEMOTHERAPY IN A PATIENT WITH AGGRESSIVE FIBROMATOSIS

Joanna Vitfell-Rasmussen, R.M. Sandvik, K. Gehl, A. Krarup-Hansen, Oncology, Herlev University Hospital, Herlev, DENMARK; K. Dahlstrøm, Plastic Surgery, Herlev University Hospital, Herlev, DENMARK; G. Al-Farra, Radiology, Herlev University Hospital, Herlev, DENMARK

Objective: Aggressive fibromatosis also known as desmoid tumors constitute 3% of soft tissue tumors. It is a monoclonal (myo-) fibroblastic proliferation derived from mesenchymal progenitor cells. These tumors commonly develop in the fibrous (connective) tissue of the body that forms tendons and ligaments, usually in the arms, legs or midsection but also in the head and neck area. Electrochemotherapy (the use of brief electric pulses to enhance uptake of chemotherapy) is increasingly being used to treat cutaneous and subcutaneous tumors of different histologies, however the use for aggressive fibromatosis has not previously been reported in humans.Methods: This case report describes a 63-year old woman with subcutaneous aggressive fibromatosis in the neck region of which the main symptom was severe pain, despite medication. At diagnosis, surgery was not feasible and radiotherapy not performed due to the diagnosis of familial adenomatous polyposis. Previous treatments included NSAID, endocrine therapy and sorafenib, which the patient had to stop due to severe side effects. After thorough consideration and discussion of various treatment options, the patient was referred for consideration of electrochemotherapy. She was informed that electrochemotherapy was considered experimental treatment in her particular case and consented to treatment. The patient was treated twice with electrochemotherapy with a 5 month interval, with 26.000 international units (IU) of bleomycin (15.000 IU/m2) and 64 pulse sequences of each eight pulses were administered using a square wave pulse generator (Cliniporator, IGEA, Carpi, Italy), and linear array electrodes. See figure 1.Results: At one year follow-up substantial tumor reduction (7.1 x 2.2 cm to 2.9 x 1.7 cm) was observed both clinically and on MRI, and the patient went from reporting severe pain, NRS (numeric rating scale) score 7 to mild pain, NRS score 2 without pain medication. See figure 2. Side effects to the treatment with electrochemotherapy were considered mild and consisted of pain, inflammation and hyperpigmentation of the treated skin area.Conclusion: This case study opens up the possibility of treating aggressive fibromatosis close to the skin with electrochemotherapy, and warrants phase II studies to investigate clinical outcomes in greater detail.

IONIZING RADIATION ENHANCES THE SENSITIVITY OF DESMOID TUMOR CTNNB1 S45F MUTANT TO SORAFENIB

Feng Jin, S. Savinoff, M. Welliver, Radiation Oncology, The Ohio State University, Columbus, Ohio, USA; D. Braggio, D. Lev, R. Pollock, The Comprehensive Cancer Center, Columbus, Ohio, USA

Objective: To test whether sorafenib or radiotherapy (RT) are effective agents for DT with S45F mutation, and whether the combination of RT with Sorafenib is additive or synergistic treatment.Methods: We treated the desmoid cell strains isolated from patient tumors with various doses of sorafenib, radiation or both and examined the cell survival with soft agar assays.Results: Both the wild type and S45F mutant DT cell lines responded well to radiation in a dose-dependent manner. Sorafenib significantly inhibited capacity of colony formation and cell proliferation of mutant DT cells, but had no notable effect on the wide type cells. The CTNNB1 S45F mutant cells also showed the sensitivity to Sorafenib in a dose-dependent manner. Combination treatment of Sorafenib and radiation resulted in additive effects on cellular anchorage-independent growth.Conclusion: A combination treatment of Sorafenib and radiation could be good strategy for the treatment of desmoid tumor patients and clinical trials should be explored.

MRI FEATURES PREDICTIVE OF RESPONSE TO METHOTREXATE AND VINORELBINE IN DESMOID FIBROMATOSIS 

Sally Burtenshaw, A. Olteanu, R. Gladdy, General Surgery, Mount Sinai Hospital, Toronto, Ontario, CANADA; A.A. Gupta, Medical Oncology, Princess Margaret Cancer Centre, Canada, Ontario, CANADA; S. Thipphavong, Medical Imaging, Princess Margaret Cancer Centre, Toronto, Ontario, CANADA

Objective: Desmoid fibromatosis (DF) is a mesenchymal tumor that is locally aggressive and historically treated with surgical resection, with high recurrence rates. Systemic treatment of progressive DF can be associated with improved progression-free rates however the use of medical therapy remains controversial. Also, treatment response as defined by RECIST 1.1 by measuring maximum tumor dimension (Dmax) may not accurately evaluate response to medical treatment in desmoid patients. We sought to assess if imaging parameters such as approximate tumor volume (Vtumor) and MRI features, specifically T2 signal were more predictive of response to medical therapy than Dmax.Methods: A retrospective chart review between 1997 and 2015 identified 22 patients with biopsy proven DF treated with Methotrexate and Vinorelbine and followed with MRI throughout treatment. Dmax, Vtumor and quantitative T2 hyperintensity using interquartile range scoring on MRI were compared pre, mid (between 3-9 months) and post-treatment. On T2-weighted or T2-weighted fat-saturated MRI images, tumors were ranked as containing: 0-25%, 25-50%, 50-75% or 75-100% of internal high T2-signal intensity. Treatment response was defined as: partial response (PR) if the size or T2 quartile score decreased, stable disease (SD) if there was no change in size or T2 quartile, progression of disease (PD) if there was an increase in size or increase in T2 quartile, and complete response (CR) if size decreased and/or the entire lesion was hypointense on T2-weighted images.Results: Mean age was 31 yrs with 17 females and 5 males. Patients presented with primary (n=18) or recurrent/residual (n=4) with DF of the extremity (n=9), abdominal wall (n=7), head and neck (n=3), chest wall/back (n=2) or mesentery (n=1). At end of treatment (median 20 mos (range 9-27)), Dmax mean decreased by -30% and Vtumor decreased by -76% overall. On T2 weighted imaging, CR was observed in 13 and PR in 5 patients. Mid treatment, 2 had PD and 7 had SD as per Dmax and Vtumor with T2 change indicative of PR in all cases. Both patients with PD continued therapy and had CR at end of treatment. Four patients progressed post treatment, median PFS was 31 months (95% CI: 14.9-137) and all had complete response (CR) on T2 imaging treatment end.Conclusion: Evaluation of treatment response for DF utilizing an estimated volume of tumor and monitoring the degree of T2-weighted signal intensity change within the tumor may be better predictors of response to medical therapy than maximum tumor dimension. Findings from this study warrant prospective multi-institutional validation.

DIFFERENTIATION OF ENDOMETRIOMAS AND DESMOIDS IN THE ANTERIOR ABDOMINAL WALL IN FEMALES OF REPRODUCTIVE AGE

Nolan Walker, P. Lykoudis, P. Dileo, M. Novelli, A. Shankar, J.T. Lordan, Sarcoma Surgery, Royal Free London and University College London, London, UNITED KINGDOM

Objective: Desmoids and endometriomas are rare, predominantly present in females of reproductive age. Endometriomas maybe be left in situ and often atrophy during pregnancy and post-menopause, unlike desmoids. Endometriomas rarely recur after excision, whereas desmoids frequently recur and so often require extensive resection. Differentiation prior to management is essential. This study was designed to determine distinguishing clinical and radiological features between desmoids and endometriomas of the anterior abdominal wall.Methods: This was a retrospective comparative analysis over eleven years (January 2006 to December 2016) in a high volume sarcoma centre. Patients with endometriomas (n=27) and desmoids (n=110) were identified. The inclusion criteria were; female, reproductive age, anterior abdominal wall, inferior to the umbilicus. Patients were excluded if there were inadequate records of radiological or clinical features. Endometriomas (n=23) and desmoids (n=19) were compared. Radiological features included; size, location (subcutaneous v intramuscular), magnetic resonance imaging T1 and T2 signal, restriction diffusion imaging, imaging characteristics (heterogenous/homogenous, internal fluid locules), and border definition. Continuous data were reported as means with p values from Paired T tests, and categorical data reported as percentages and p values from McNemar or Fishers exact tests.Results: Clinically, 50% of patients with endometriomas reported cyclical symptoms, compared with zero patients with desmoids (p=0.007). The mean age for patients with desmoids and endometriomas was 34 years and 37 years respectively (p=0.71). Mean tumour size of desmoids and endometriomas was 6.8cm and 3.1cm respectively (p<0.0001). 70% of endometriomas and 58% of desmoids were heterogenous (p=0.32). Desmoids had a greater incidence of internal fluid locules (93% v 50%, p=0.03). There was no difference in exhibition of bright T2 areas (75% v 53%, p=0.19) between desmoids and endometriomas respectively. There was a greater number of desmoids with a low T1 signal (88% v 53%, p=0.04). All desmoids and endometriomas exhibited restricted diffusion and enhancement.Conclusion: Endometriomas and desmoids occur infrequently and can be challenging to differentiate. However, endometriomas may be associated with smaller size and cyclical pain, while desmoids may have a greater incidence of low T1 signal. We recommend obtaining histological or cytological diagnosis prior to management

HIGH THROUGHPUT GENOME STUDY TO IDENTIFY PREDICTORS OF AGGRESSIVENESS IN PATIENTS WITH SPORADIC DESMOID TUMOR WHO UNDERGO A WAIT AND SEE APPROACH

Chiara Colombo, M. Fiore, A. Gronchi, Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ITALY; M. Urbini, A. Astolfi, V. Indio, M. Pantaleo, “Giorgio Prodi” Cancer Research Center, Bologna, ITALY; P. Collini, A. Belfiore, N. Paielli, F. Perrone, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ITALY

Objective: Wait and see approach for desmoid-type fibromatosis (DF) patients has become part of the routine treatment strategy. Two parallel European prospective studies have been conducted to validate this approach. However, predictive factors to select the risk of progressive disease in the individual patient are still lacking. A translational project was run in order to identify genomic signatures associated to specific behaviors in patients enrolled within the Italian prospective observational study.Methods: DF fresh frozen samples from enrolled patients who have been biopsied at our Institution were collected for translational studies. Whole exome sequencing was performed on DNA extracted from 12 fresh frozen biopsies using Nextseq500 (Illumina, CA) sequencer. Deep sequencing of CTNNB1, APC and LAMTOR2 was performed on additional 12 FFPE cases of WT DF using Truseq custom amplicon low input kit (illumina) for library preparation and sequenced on MiSeq instrument (illumina).Results: Twelve fresh frozen biopsies were analyzed through exome sequencing. Using Sanger sequencing 10 mutated DF (8 T41A and 2 S45F) and 2 WT were identified. In WT cases, two genes were found to be mutated: APC in one case (p.D1696N and p.D1670H) and LAMTOR2 (p.V92M) in the other. Globally, DF exhibited low somatic sequence mutation rate (mean 0.36 mutations per megabase), and in the CTNNB1-mutated group no other recurrent mutational event was identified. Overall, in this group, only 2/12 patients (17%) were shifted from an observational approach to a specific treatment for progressive disease. In order to enlarge the study on WT DF subtype and identified new potential mutations, high deep sequencing of CTNNB1, APC and LAMTOR2 was conducted on a retrospective series of 12 additional WT DF. No other mutation of LAMTOR2 was detected. APC mutation was detected in one case, while low-frequencies CTNNB1 mutations were found in 6 samples (50%) (mean of 16% reads). However, 5 cases (42%) remained WT for CTNNB1 or APC mutations. Further analyses are ongoing in this subgroup to identify other potential molecular events determining tumorigenesis.Conclusion: DF is characterized by a low load of mutational events, which do not seem to be associated to the clinical course of the disease. A minority of DF is wild type for either CTNNB1, APC or any other gene involved in the WNT pathway. The clinical and molecular meanings of these findings need further investigation.

TREATMENT AND PROGNOSIS OF DESMOID TUMORS: A SINGLE INSTITUTIONAL EXPERIENCE OF 189 PATIENTS

Jaekyung Cheon, Ulsan University Hospital, Ulsan, KOREA (THE REPUBLIC OF); J. Kim, J. Ahn, Asan Medical Center, Seoul, KOREA (THE REPUBLIC OF)

Objective: Desmoid tumors (DTs) are locally infiltrating soft-tissue neoplasm that grow slowly and arise from musculoaponeurotic stromal elements. DTs usually occurs sporadically but 5~10% of them are associated with familial adenomatous polyposis (FAP). Because of rarity of DTs, there are relatively few data on its epidemiology and long term outcomes.Methods: We analyzed the data of 189 patients who were diagnosed as DT from October 1992 to August 2015 using Asan Medical Center Sarcoma Registry. Clinicopathologic features and treatment related data were analyzed to identify predictive factor for recurrence.Results: A total of 189 patients were included for the analysis. The median age of patients was 39 years old (range, 0-96) and 108 patients (57.1%) were female. Familial history of FAP was present in 13 patients (6.8%). The most common primary tumor site was abdominal wall (38.1%), followed by the abdominal cavity (34.9%), retroperitoneum (15.8%) and extremities (5.3%). The median tumor size was 5.0 cm (range, 0.5-25.0 cm). Among 177 patients who underwent treatments, 165 patients (93.2%) received surgery, 11 patients received systemic therapy and one patient underwent radiotherapy for the 1st line treatment. Majority of patients who underwent surgery, had R0, R1 surgical margin (46.1%, 44.8%, respectively). With a median follow-up of 29.7 months, 15 patients (7.9%) showed recurrence after surgery within a median time interval of 15.5 months. In univariate analysis, sex, age, tumor size, tumor location, and surgical margin had no significant impact on recurrence. Out of 15 patients with recurrence, 3 patients had familial history of FAP. When patients were divided into 3 groups according to primary site: abdominal wall, intraabdominal, extraabdominal group, the number of patients with recurrent disease were 5, 4, and 6 (7.0%, 6.0% and 11.8% respectively). Of the 6 recurrent cases in which the primary site was located in the extraabdominal region, 3 patients showed 2nd recurrence, and they underwent resection. Two of 3 patients with 2nd recurrence had 3rd recurrence.Conclusion: Recurrence remains a problem following surgery of DTs. In the patients with extraabdominal site DTs, the recurrence rate tends to be higher. These patients may recur again even after curative surgical resection, therefore careful follow up is required.

Miscellaneous

“Molecular Insights Into Desmoid Tumors” by Nam Bui and Shivaani Kummar.

“Locally Aggressive Connective Tissue Tumors”, Journal of Clinical Oncology, Mrinal M. Gounder and William D. Tap, Memorial Sloan Kettering Cancer Center and Weil Cornell Medical School, New York, NY; and David M. Thomas, Garvan Institute of Medical Research, Darlinghurst, Australia.

An update on the management of sporadic desmoid-type fibromatosis: a European Consensus Initiative between Sarcoma PAtients EuroNet (SPAEN) and European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG)

Abstract: Desmoid-type fibromatosis (DF) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Currently, there is no established or evidence-based treatment approach available for this disease. Therefore, in 2015 the European Desmoid Working Group published a position paper giving recommendations on the treatment of this intriguing disease. Here, we present an update of this consensus approach based on professionals’ AND patients’ expertise following a round table meeting bringing together sarcoma experts from the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) with patients and patient advocates from Sarcoma Patients EuroNet (SPAEN). In this paper, we focus on new findings regarding the prognostic value of mutational analysis in DF patients and new systemic treatment options.

Long-Term Follow-Up of Desmoid Fibromatosis Treated with PF- 03084014, an Oral Gamma Secretase Inhibitor, Victor Villalobos, MD, PhD, University of Colorado-Denver

“Biology & Treatment of Aggressive Fibromatosis or Desmoid Tumor”, Keith Skubitz, MD  

Childhood Soft Tissue Sarcoma Treatment (PDQ®): Health Professional Version

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood soft tissue sarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Abdominal Wall Reconstruction

Abdominal wall reconstruction has become a frequently used term to describe hernia repairs that try to recreate the abdominal wall and restore function and structure. Although there has been no true definition of a functional abdominal wall, many surgeons believe this involves the closure of the fascia at the midline often with reinforcement using mesh prosthetics. The integrity of the abdominal wall is vital as it serves to protect the internal organs, supports the spine and helps maintain an upright posture. Several tumors can occur on the abdominal wall, and the most common are desmoid tumors. These lesions even though histologically benign, often are very locally invasive. Treatment of desmoids often requires full thickness abdominal wall excision. Despite this, local recurrence rates are nearly 40% to 50%. Most of these recurrences occur within the first 24 months after surgery. In some cases, adjuvant radiation therapy is recommended especially when the margins are not clear. Management of malignant lesions of the abdominal wall requires aggressive resection of the subcutaneous tissues and skin, as well as any involved muscle. Sarcomas are the most common tumors of the abdominal wall and require aggressive resection, followed by radiotherapy. There may also be some intraabdominal wall tumors either via hematogenous or contiguous spread that require resection. Reconstruction of the abdominal wall in these cases is usually directed by the extent of resection and the possibility of further surgical intervention.

2016 DTRF Patient Meeting Presentations

View presentations here.

2016 DTRF Research Workshop Presentations

View presentations here.

2016 ASCO Annual Meeting

Abstracts

  • Geraldine Helen O’Sullivan Coyne, Shivaani Kummar, Khanh Tu Do, Peter L. Choyke, Baris Turkbey, Eric Polley, Yvonne Horneffer, Lamin Juwara, Rasa J Vilimas, Robert S. Meehan, Lee J. Helman, James H. Doroshow, Alice P. Chen; Early Clinical Trials Development Program, DCTD, National Cancer Institute at the National Institutes of Health, Bethesda, MD; National Cancer Institute, Bethesda, MD; Dana-Farber Cancer Center/Brigham and Women’s Hospital, Boston, MA; National Cancer Institute at the National Institutes of Health, Bethesda, MD; Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD; Mayo Clinic, Rochester, MN; Leidos BioMedical Research, Inc, Bethesda, MD; Early Clinical Trials Development Program, DCTD, NCI, Bethesda, MD; Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD; Division of Cancer Treatment and Diagnosis, NCI, NIH, Bethesda, MD; Early Clinical Trials Development Program, National Cancer Institute at the National Institutes of Health, Bethesda, MD
    Activity of PF-03084014 in adults with desmoid tumors/aggressive fibromatosis.

 

 

  • Olivier Mir, Chahinez Rahal, Françoise Rimareix, Julien Adam, Philippe Terrier, Julien Domont, Sarah Dumont, Arslane Skander Rahal, Andrea Cavalcanti, Isabelle Sourrouille, Nicolas Leymarie, Charles Court, Gilles Missenard, Leila Haddag-Miliani, Charles Honoré, Axel Le Cesne; Gustave Roussy Cancer Campus, Department of Medical Oncology, Villejuif, France; Gustave Roussy Cancer Campus, Villejuif, France; Department of Biopathology, Gustave Roussy Cancer Center, Villejuif, France
    Efficacy of oral vinorelbine in advanced/progressive desmoid tumours: An updated retrospective study in 50 patients.

 

 

  • Rodrigo Ramella Munhoz, Robert A Lefkowitz, Deborah Kuk, Mark Andrew Dickson, Sandra P. D’Angelo, Mary Louise Keohan, Ping Chi, Aimee Marie Crago, Robert G. Maki, Gary K. Schwartz, Li-Xuan Qin, William D. Tap, Mrinal M. Gounder; Hospital Sírio Libanês, São Paulo, Brazil; Memorial Sloan Kettering Cancer Center, New York, NY; Icahn School of Medicine at Mount Sinai, New York, NY; Columbia University Medical Center – New York Presbyterian Hospital, New York, NY
    Efficacy of sorafenib in patients with desmoid-type fibromatosis.

 

 

Posters

  • Rodrigo Ramella Munhoz, Robert A Lefkowitz, Deborah Kuk, Mark Andrew Dickson, Sandra P. D’Angelo, Mary Louise Keohan, Ping Chi, Aimee Marie Crago, Robert G. Maki, Gary K. Schwartz, Li-Xuan Qin, William D. Tap, Mrinal M. Gounder; Hospital Sírio Libanês, São Paulo, Brazil; Memorial Sloan Kettering Cancer Center, New York, NY; Icahn School of Medicine at Mount Sinai, New York, NY; Columbia University Medical Center – New York Presbyterian Hospital, New York, NY
    Efficacy of sorafenib in patients with desmoid-type fibromatosis.”

 

  • Geraldine Helen O’Sullivan Coyne, Shivaani Kummar, Khanh Tu Do, Peter L. Choyke, Baris Turkbey, Eric Polley, Yvonne Horneffer, Lamin Juwara, Rasa J Vilimas, Robert S. Meehan, Lee J. Helman, James H. Doroshow, Alice P. Chen; Early Clinical Trials Development Program, DCTD, National Cancer Institute at the National Institutes of Health, Bethesda, MD; National Cancer Institute, Bethesda, MD; Dana-Farber Cancer Center/Brigham and Women’s Hospital, Boston, MA; National Cancer Institute at the National Institutes of Health, Bethesda, MD; Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD; Mayo Clinic, Rochester, MN; Leidos BioMedical Research, Inc, Bethesda, MD; Early Clinical Trials Development Program, DCTD, NCI, Bethesda, MD; Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD; Division of Cancer Treatment and Diagnosis, NCI, NIH, Bethesda, MD; Early Clinical Trials Development Program, National Cancer Institute at the National Institutes of Health, Bethesda, MD
    Activity of PF-03084014 in adults with desmoid tumors/aggressive fibromatosis.

 

2016 CTOS Meeting

Abstract

 

 

Paper

 

Presentation

 

 

Miscellaneous

  • Dr. Bernd Kasper of Mannheim University Medical Center
    Brief video followup on “Clinical and translational research results of a phase II study evaluating imatinib to induce progression arrest in RECIST progressive desmoid tumors- A study of the German Interdisciplinary Sarcoma Group (GISG- 01)”

2015 DTRF Patient Meeting Presentations

View presentations here.

2015 DTRF Research Workshop Presentations

View presentations here.

2015 CTOS Meeting

  • Jacob Bickels, MD, Orthopaedic Oncology, Sourasky Medical Center, Israel
    Poster: “Aminolevulinic acid photoablation of fibrotic soft-tissue tumors: preliminary report of 24 patients.”

 

  • Chiara Colombo, MD, Surgical Oncology, Fondazione IRCCS Istituto Tumori di Milano
    Poster: “Gene expression analysis identifies a potential role of immune system in CTNNB1 mutated desmoid tumors.”

 

  • Amanda Kirane, MD, Surgery, Memorial Sloan Kettering Cancer Center
    Poster: “Progression of desmoid-type fibromatosis during active observation is associated with tumor size.”
    Poster: “Molecular characterization of desmoid tumors.”

2013 SPAEN Conference

 

 

 

 

Miscellaneous

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